We propose to develop new kappa opioid receptor (KOR) modulators for early stage development towards treating addictive and mood disorders. Dynorphins are stress peptides and act at the KOR. Therefore, to suppress dynorphin-mediated effects, negative regulators of KOR are sought. There is considerable evidence that KOR signals through ?arrestin2 to mediate certain side effects (sedation and dysphoria) and through G proteins to mediate its analgesic and antipruritic effects. Therefore, we propose to develop compounds that antagonize the ?arrestin2-interacting receptor. Specifically we aim to deliver: 1. Competitive antagonists that are potent and efficacious in suppressing ?arrestin2 recruitment; 2. Partial agonists that are potently competitive at blocking dynorphin-stimulated ?arrestin2 recruitment while preserving full agonism in G protein signaling; 3. Negative allosteric modulators that will decrease KOR responsiveness to dynorphins. In this proposal, we present an update on the extensive progress we have made in introducing the first small molecule, G protein biased KOR agonists to the field. We also provide substantial preliminary data supporting a successful campaign to develop the aforementioned antagonists, biased partial agonists and negative allosteric modulators. In particular, the negative allosteric modulators will be first in class for this receptor. This proposal seeks 5 years of support to provide the initia preclinical characterizations and chemical optimizations of these compounds into drug candidates. In line with this goal, we will fully characterize the pharmacological properties of th compounds across functionally diverse cell-based assays with of a goal of identifying compounds capable of fine-tuning KOR responsiveness. Cell-based responses will be validated in mouse models assessing locomotor responses, antinociceptive activity and suppressing pruritis (itch response) to determine that compound maintains the pharmacological profiles in vivo. Drug metabolism and pharmacokinetics of the compounds will be performed to provide information for continued medicinal chemistry optimization rounds and to advance compounds to clinical development. Our enthusiastic team consists of established medicinal and synthetic chemists; an opioid neuropharmacologist (with both molecular and behavioral pharmacology expertise); and an expert in pharmacokinetics and drug metabolism. The development of pharmacological tools across diverse pharmacophores and correlating their properties with in vivo response profiles will provide guiding evidence of the optimal chemical and pharmacological properties required to produce the desired physiological responses.